The primary long-term objective of this program project is the elucidation of the etiology and pathogenesis of Parkinson's disease and related disorders. The research during the next five years of this proposal will continue to focus on studies designed to determine the modus operandi of 1-methy1-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and several of its structural analogs. Many of these analogs, which resulted from research conducted in the first two years of the original proposal, are as potent or even more potent as dopaminergic neurotoxins than is MPTP itself. Two examples of very neurotoxic analogs are 2'methyl-MPTP and 2' ethyl-MPTP, both of which are bioactivated at least in part by monoamine oxidase-A. This contrasts with MPTP, which is bioactivated predominantly (but not exclusively) by MA0-B. Research will focus on determining if our previously published "mitochondrial hypothesis" may account for the neurotoxic actions of MPTP. This hypothesis is based on our observations made in the original grant period that 1-methy1-4- phenylpyridinium (MPP+) is a potent and selective inhibitor of Complex I mitochondrial respiration. Strikingly, all of the MPTP analogs that we have found to be neurotoxic are oxidized by monoamine oxidase to pyridinium metabolites that also inhibit mitochondrial respiration. The newly added research will focus on the development and utilization of somatic cell replacement therapy in animal models of Parkinson's disease including the MPTP-treated mouse. More specific details can be obtained in the abstracts to the individual projects.